Altered lipid profile in mice lacking the DNA repair protein ERCC1.

Mutations in the Ercc1 gene, essential for DNA repair, are associated with accelerated aging and metabolic disturbances, but data on lipid composition under its deficiency remain limited. To address this gap, we analyzed the fatty acid (FA) profiles and lipids of the mevalonate pathway in mouse embryonic fibroblasts (MEFs) and in brains, livers, and kidneys of Ercc1-/- and wild-type (WT) mice. Ercc1-/- MEFs showed significantly reduced FA levels, while in brains and livers, differences vs. WT were not significant, though males tended to have lower values. Isoprenoids exhibited more pronounced changes. Squalene content was higher in Ercc1-/- MEFs and in female brains. Meanwhile, cholesterol levels decreased in MEFs and male brains but increased in livers. These findings indicate tissue- and sex-specific disruptions of sterol homeostasis. Notably, dolichols, recognized markers of aging, were significantly elevated in the brains and livers of Ercc1-/- mice, accompanied by shifts in their chain-length distribution. Only subtle sex-dependent differences were observed in the kidneys, without consistent changes in sterol, cholesterol and dolichol levels. Gene expression analysis partially supported these findings. In brains, Srd5a3 upregulation corresponded with dolichol accumulation; however, reduced Dhcr24 expression did not lower cholesterol levels. In livers, increased NgBR and Dhdds expression corresponded with higher dolichol levels. Kidneys displayed broad downregulation of mevalonate pathway genes, yet metabolite levels remained essentially unchanged. Overall, Ercc1 deficiency causes significant tissue- and sex-dependent disturbances in lipid metabolism, particularly affecting dolichol synthesis. Such alterations may contribute to the hallmarks of accelerated aging and neurodegeneration, associated with impaired DNA repair.